The RNA‐binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors

Abstract

The RNA-binding protein HuR promotes tumor growth by affecting proliferation, metastasis, apoptosis, and angiogenesis. Although immune cells, especially tumor-associated macrophages, are critical components of the tumor stroma, the influence of HuR in tumors on the recruitment of immune cells remains poorly understood. In the present study, we, therefore, aimed to elucidate the impact of tumor cell HuR on the interaction between tumor cells and macrophages. To this end, we stably depleted HuR in human MCF-7 breast cancer cells. We found that HuR-deficient cells not only showed reduced proliferation, they further expressed elevated levels of the chemokine CCL5. HuR-dependent repression of CCL5 was neither caused by altered CCL5 mRNA stability, nor by changes in CCL5 translation. Instead, loss of HuR augmented transcription of CCL5, which was mediated via an interferon-stimulated response element in the CCL5 promoter. Furthermore, HuR depletion enhanced macrophage recruitment into MCF-7 tumor spheroids, an effect which was completely lost upon neutralization of CCL5. HuR expression further negatively correlated with CCL5 expression and macrophage appearance in a cohort of breast tumors. Thus, while HuR is well-characterized to support various pro-tumorigenic features in tumor cells, we provide evidence that it limits the recruitment of macrophages into tumors by repressing CCL5. As macrophage infiltration is associated with poor prognosis, our findings underline the highly cell-type and context specific role of HuR in tumorigenesis.

Macrophages attenuate the transcription of CYP1A1 in breast tumor cells and enhance their proliferation

“…In order to explore how MФs influence tumor cells, we grew MCF7 breast tumor cells as three-dimensional tumor spheroids. After 5 days, the MCF7 tumor spheroids began to develop a characteristic necrotic core (Fig 1A) [15, 16], thus providing an in vitro proxy for the situation in vivo . Subsequently, CD14 + cells, i.e.…”

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…CCL5 not only affects cancer cells but also tumor-associated cells. It recruits MDSC [ 88 , 89 ], MSC [ 90 ], TAM [ 77 , 91 , 92 ], and T-helper cells 17 (Th17) [ 93 ] into the tumor niche. Via CCR5, it participates in recruiting T reg and elevating its activity in the tumor niche [ 67 , 94 , 95 , 96 ].…”

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…An important function of chemokines in cancer is to support the course of angiogenesis [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ] and lymphangiogenesis [ 15 , 20 , 21 , 22 , 23 , 24 ]. Another important role of chemokines in cancer processes is the recruitment of cells to a cancer niche, in particular cancer-associated fibroblasts (CAF) [ 25 , 26 ], eosinophils [ 27 , 28 , 29 ], regulatory T cells (T reg ) [ 30 , 31 , 32 , 33 , 34 ], T helper type 17 (Th17) [ 35 , 36 , 37 ], tumor-associated neutrophils (TAN) [ 38 ], tumor-associated macrophages (TAM) [ 11 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and myeloid-derived suppressor cells (MDSC) [ 48 ]. However, some chemokines exert anti-cancer effects by causing tumor-infiltrating lymphocytes (TIL) infiltration, in particular CC motif chemokine ligand (CCL)2/monocyte chemoattractant protein (MCP)-1 [ 49 , 50 , 51 , 52 , …”